New Treatment Strategies in Patients with Advanced Non–Small-Cell Lung Cancer and Performance Status 2

mini-review New Treatment Strategies in Patients with Advanced Non–Small-Cell Lung Cancer and Performance Status 2 Estelamari Rodriguez, Rogerio C. Lilenbaum Clinical Lung Cancer, Vol. 9, No. 6, 326-330, 2008; DOI: 10.3816/CLC.2008.n.047 Keywords: Monoclonal antibodies, Platinum agents, Taxanes, Tyrosine kinase inhibitors

Abstract Patients with performance status (PS) 2 represent approximately 30%-40% of all patients with advanced non–small-cell lung cancer (NSCLC) seen in clinical practice. Although these patients have been historically excluded from randomized clinical trials, recent studies have suggested a benefit from systemic chemotherapy. The development of biologic agents offers a new promise for the treatment of PS 2 patients as a result of the perceived improved therapeutic index of these agents. However, many of the recent advances in NSCLC have been limited to good PS patients and have not translated into an improvement in the management of the PS 2 population because the studies have excluded this patient population or have failed to demonstrate a survival benefit.

Introduction Lung cancer is the leading cause of cancer-related deaths in the United States, with  160,000 deaths expected in 2008.1 Patients with less than optimal PS represent 30%-40% of all patients with advanced non–small-cell lung cancer (NSCLC)2-4 and experience a significantly poorer outcome.5-7 Given concerns about lack of efficacy and excess toxicity, these patients are less often treated with chemotherapy. The development of clinical trials specifically focusing on PS 2 patients with advanced NSCLC is a recent trend.8-13 Although studies testing Address for correspondence: Rogerio C. Lilenbaum, MD, Mount Sinai Cancer Center, Miami Beach, FL 33140 Fax: 305-535-3324; e-mail: [email protected]

third-generation regimens have reported improved outcomes and less treatmentrelated complications, the treatment of PS 2 patients remains a vexing issue in thoracic oncology. The advent of molecular targeted agents, such as epidermal growth factor receptor (EGFR) antagonists and antiangiogenic agents, has led to improved outcomes for patients with advanced NSCLC. However, apart from a few notable exceptions, patients with PS 2 have been largely excluded from these trials. As a consequence, these innovative treatments have not been uniformly incorporated into the management of PS 2 patients, whose poor prognosis has not been substantially altered in the past decade.

Standard Chemotherapy There is currently no standard of care for PS 2 patients with advanced NSCLC. Several different approaches have been studied, including single-agent chemotherapy, platinum-based doublets, and non–platinumcontaining regimens (Table 1). In trials comparing single-agent with combination chemotherapy, combination regimens appear to increase response rates and progressionfree survival (PFS) with manageable toxicities. A planned subset analysis of the 99 patients with PS 2 in the CALGB 9730 trial, which randomized patients to receive carboplatin and paclitaxel versus paclitaxel alone, showed that PS 2 patients who received the combination had significantly better response rates (24% versus 10%), median survival times (4.7 months versus

2.4 months), and 1-year survival rates (18% versus 10%) than those treated with singleagent therapy.10 In fact, the magnitude of the benefit for combination chemotherapy was greater in the PS 2 subset than in the PS 0-1 patients, suggesting a more discernible impact of combination chemotherapy in patients with more aggressive and rapidly progressive disease. Preliminary results from a recent US Oncology phase III study of single-agent gemcitabine versus carboplatin-gemcitabine in PS 2 patients confirmed the trend for better efficacy with combination chemotherapy.11 Although the study was terminated before completing accrual, both response rate (36% versus 12%) and PFS (4.0 months versus 2.8 months) were significantly superior for carboplatin-gemcitabine, whereas the difference in overall survival did not reach statistical significance (6.9 months versus 5.2 months). As expected, grade 3/4 hematologic toxicities were increased in the combination arm, but quality of life parameters trended better with the combination regimen. The largest dedicated phase III trials, STELLAR 3 and STELLAR 4, randomized  700 PS 2 patients to single-agent paclitaxel poliglumex (PPX) versus gemcitabine or vinorelbine and to carboplatin-PPX versus carboplatin-paclitaxel (Table 1). The experimental arm (PPX) did not show an advantage over the standard arm in either study.12-13 The STELLAR trials offer valuable information regarding PS 2 patients treated with systemic chemotherapy. In a multivariate regression analysis, low albumin, extrathoracic metastases excluding brain,  2 comorbidities, and a smoking history were

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mini-review Table 1: Selected First-Line Chemotherapy Trials in Patients with Advanced Non–Small-Cell Lung Cancer with PS 2 Study

Lilenbaum10 CALGB 9730 (Prospective Subset Analysis)

Langer12 STELLAR-3

O’Brien13 STELLAR-4

Phase

No. of Patients with PS 2 (Total)

III

99 PS 2 (284)

III

400

Drug Regimen

RR, %

Survival

Carboplatin AUC 6 + Paclitaxel

24

MS, 4.7 months 1-year OS, 18%

Paclitaxel

10

MS, 2.4 months 1 year OS, 10%

Carboplatin AUC 6 + Paclitaxel 225 mg/m2 Q3 vs.

36

MS, 5.8 months 1-year OS, 19%

Carboplatin AUC 6 + PPX 210 mg/m2 Q3

21

MS, 7.2 months 1-year OS, 28%

PPX 175 mg/m2 Q3

11

MS, 7.3 months 1-year OS, 26%

15

MS, 6.6 months 1-year OS, 28%

Gemcitabine 1250 mg/m2 d 1, 8 Q3W vs.

12

MS, 5.2 months 1-year OS, 24%

Gemcitabine 1000 mg/m2 d 1, 8 + Carboplatin AUC 5 d 1 Q3W

36

MS, 6.9 months 1-year OS, 31%

vs.

vs. III

378

Gemcitabine 1000 mg/m2 d 1, 8, 15 Q4 or Vinorelbine 30 mg/m2 d 1, 8, 15 Q4

Obasaju11 US Oncology

III

161

Abbreviations: MS = median survival; OS = overall survival; PPX = paclitaxel poliglumex; PS = performance status; RR = response rate

found to be significant predictors of worse prognosis. When grouped according to the number of adverse prognostic factors, patients in the high-risk category seemed to benefit from combination chemotherapy, whereas patients in the low-risk category fared equally with single-agent or combination chemotherapy.14 This is the first attempt to stratify and manage PS 2 patients according to a specific prognostic model and additional validation of the model, in different populations, is warranted. On the basis of the CALGB subset analysis, the US Oncology trial, and the combined analysis of the STELLAR trials, combination chemotherapy increases response rates and prolongs PFS compared with single-agent therapy, without a detriment to quality of life in selected PS 2 patients. However, a clear impact on overall survival has not been demonstrated. An ongoing phase III trial comparing pemetrexed alone with carboplatinpemetrexed in PS 2 patients, conducted in Brazil, will hopefully provide a definitive answer to this question.

Although there are compelling data supporting the use of combination chemotherapy in PS 2 patients, there is still debate regarding the use of singleagent chemotherapy.15,16 The National Comprehensive Cancer Network and a panel of European experts have concluded that chemotherapy is justified in PS 2 patients and that a single agent is generally preferred, but carboplatin-based doublets are a reasonable alternative in selected cases.17,18

Targeted Therapy Epidermal Growth Factor Receptor Inhibitors At first glance, biologic agents appear to be an ideal treatment choice for PS 2 patients on the basis of their more selective targets, lower toxicity profile, and convenient oral formulation. Erlotinib, an EGFR oral tyrosine kinase inhibitor (TKI), was approved for second- and third-line treatment of advanced NSCLC on the basis of results of the BR21 study, which included patients with PS 0-3.19 Erlotinib was shown to improve survival, tumor-related symptoms, and overall

quality of life.20 The efficacy of erlotinib was independent of performance status and persisted across the PS 2-3 strata. However, studies of erlotinib as firstline therapy for PS 2 patients have yielded disappointing results (Table 2). The Southwest Oncology Group (SWOG) conducted a phase II trial of erlotinib in 72 untreated PS 2 patients with advanced NSCLC.21 Response rate was 8% with a median PFS of 2.1 months and median survival of 5.0 months. In a randomized phase II study of first-line erlotinib versus carboplatin/paclitaxel in patients with PS 2, those receiving erlotinib fared significantly poorer than those treated with combination chemotherapy, with a PFS of 1.9 months versus 3.5 months and median survival of 6.6 months versus 9.7 months, respectively.22 The patients who, at the time of progression, crossed over from the chemotherapy to the erlotinib arm had a median survival of 14.9 months. The absolute number of grade 3 treatment-related adverse events in the erlotinib and chemotherapy arms was comparable between 23% and 25%, but the toxicities were very different. Skin rash and

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mini-review Table 2: Selected Trials of First-Line Targeted Therapy in Patients with Advanced Non–Small-Cell Lung Cancer with PS 2 Study

Hesketh21 S0341

Lilenbaum22 (Randomized)

Goss23 INSTEP (Randomized)

Morere24 IFCT-0301 (Randomized)

No. of Patients with PS 2 (Total)

Drug Regimen

RR (SD), %

Toxicity

Survival, Months

72

Erlotinib 150 mg/day

8 (35)

Grade 3/4: Fatigue, 17% Rash, 10% Diarrhea, 7%

MS, 5 PFS, 2.1

Erlotinib 150 mg/day

4 (37)

Grade 3/4: 25% (rash, diarrhea)

MS, 6.6 PFS, 1.9

12 (43)

Grade 3/4: 37% (emesis, alopecia, neuropathy, fatigue)

MS, 9.7 PFS, 3.5

Rash: 40% vs. 11% Diarrhea: 51% vs. 20% Fatigue: 15% vs. 22%

PFS HR, 0.821 (P = .21)

Grade 4 toxicity: 4%

MS, 2.2 PFS, 1.9

14%

MS, 2.4 PFS, 2.1

38.1 (PR & SD)

11%

MS, 3.5 PFS, 2

10.5

Hematologic: 17% (docetaxel + cetuximab) vs. 17% (docetaxel + bortezomib)

MS, 3.8 PFS, 3.1

13.6

Nonhematologic: 44% (docetaxel + cetuximab) vs. 36% (docetaxel + bortezomib)

MS, 3.3 PFS, 1.8

vs.

103

Carboplatin AUC 6 + Paclitaxel 200 mg/m2 every 3 weeks

201

127 (PS 2/3)

Gefitinib 250 mg/day vs. Placebo

6

Gefitinib 250 mg/day

20.9 (PR & SD)

vs. Gemcitabine 1250 mg/m2 days 1, 8 every 3 weeks 33.4 (PR & SD) vs. Docetaxel 75 mg/m2 every 3 weeks

Lilenbaum26 CALGB 30402 (Randomized)

Gridelli25 CALC1-PS2 (Randomized)

1

55

Docetaxel 30 mg/m2 days 1, 8, 15 every 4 weeks + Cetuximab 400 mg/m2 every week vs. Docetaxel 30 mg/m2 days 1, 8, 15 every 4 weeks + Bortezomib days 1, 8, 15 every 4 weeks

42

Gemcitabine 1200 mg/m2 days 1, 8 every 3 weeks + Cetuximab 250 mg/m2 every week vs. Gemcitabine 1200 mg/m2 days 1, 8 every 3 weeks l Cetuximab 250 mg/m2 every week (60% of patients not able to start cetuximab in sequential arm)

9.1 (50)

10 (15)

Grade 3/4: Rash: 32% vs. 5% Fatigue: 9% vs. 5% Heme: 3% vs. 20%

MS, 10.3 PFS, 5.75 MS, 6.5 PFS, 2.25

Abbreviations: MS = median survival, PFS = progression-free survival; PR = partial response; PS = performance status; SD = stable disease

diarrhea were the major toxicities associated with erlotinib, while myelosuppression, emesis, peripheral neuropathy, and fatigue were more commonly reported in the chemotherapy arm. Quality of life parameters were comparable between both treatment arms. Gefitinib, another EGFR TKI, has also been tested in chemotherapy-naive PS 2 patients. The phase II study by Goss et al randomized 201 patients with PS 2 and 3 to gefitinib versus placebo.23 A preliminary analysis showed a nonsignificant trend in the primary endpoint of PFS in favor of gefitinib (HR, 0.821; 95% CI, 0.6-1.123; P = .2165). Response rates were 6% and 1% for gefitinib and placebo, respectively. Patient-reported

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outcomes, including symptom improvement, were similar for gefitinib- and placebo-treated patients. More mature results of this trial are expected in the near future. The study by Morere et al randomized 127 patients with PS 2 (69%) and PS 3 (31%) to single-agent gefitinib versus gemcitabine versus docetaxel. Although there was no significant difference in PFS or overall survival among the three treatment groups, there was a trend for an overall survival advantage in favor of the docetaxel group in PS 2 patients: 3.4 months, 3.2 months, and 6.6 months, respectively.24 Final publication of these results is also expected in the near future.

Cetuximab is an EGFR-targeted monoclonal antibody that has been tested in patients with advanced NSCLC and poor PS. Gridelli et al compared concomitant gemcitabine and cetuximab with the two agents administered sequentially in a phase II randomized trial.25 Although response rates were low in both arms (9%-10%), PFS (5.7 months) and median survival (10.3 months) were better with the concomitant treatment. Illustrative of the poor prognosis associated with a PS of 2, 60% of patients were unable to receive cetuximab after gemcitabine in the sequential arm. A randomized phase II study of weekly docetaxel plus either cetuximab

mini-review or bortezomib (CALGB 30402) in PS 2 patients showed less promising results. Respectively, response rates were 10.5% and 13.6%, PFS 3.1 months and 1.8 months, and median survival times 3.8 months and 3.3 months.26 These results did not appear to be substantially different from those achieved with weekly docetaxel alone. The fact that the CALGB and the Italian trials tested the same approach of single-agent chemotherapy in combination with cetuximab and led to different outcomes is most likely explained by the different choice of chemotherapy agents and more importantly by patient selection. This exemplifies the heterogeneity of the PS 2 patient population and the lack of current guidelines in regard to the best chemotherapy regimen to be tested in combination with targeted therapies. The phase III FLEX study randomized 1125 chemotherapy-naive patients with EGFRpositive tumors by immunohistochemistry to cetuximab in combination with cisplatin/ vinorelbine or chemotherapy alone.27 The cetuximab arm was superior to chemotherapy alone, with a median survival of 11.3 months and 10.1 months, respectively (HR, 0.871; P = .044). This study is unique in the fact that it enrolled PS 2 patients (196 of 1125), and despite an overall inferior outcome compared to PS 0/1 patients, the benefit of cetuximab in addition to chemotherapy was maintained in the PS 2 subgroup.

Antiangiogenic Agents There is an even greater paucity of data for the use of antiangiogenic agents in the treatment of PS 2 patients with advanced NSCLC. Because the toxicity profile of these agents is perceived to be more substantial than that of EGFR inhibitors, clinical research has been mostly restricted to good PS patients. The pivotal ECOG 4599 phase III trial, which demonstrated a survival benefit for the addition of bevacizumab to carboplatinpaclitaxel,28 did not include PS 2 patients, and neither did the AVAIL trial, which showed an improved PFS for bevacizumab in combination with cisplatin-gemcitabine.29 In fact, even in the second-line setting, when bevacizumab was combined with

single-agent therapy, PS 2 patients were not included.30 Ongoing studies are trying to define the safety of bevacizumab in a broader patient population, and trials to establish the safety and efficacy in PS 2 patients are urgently needed. One of these initiatives is a phase II study by the Hoosier Oncology Group, testing the combination of bevacizumab with erlotinib in chemotherapy-naive PS 2 patients.31 Several oral multitargeted TKIs with antiangiogenic properties, including vandetanib, sunitinib, sorafenib, and cediranib, are currently under investigation, alone or in combination with standard chemotherapy in advanced NSCLC. The initial phase II studies with sunitinib, sorafenib, and vandetanib, in the first- or second-line settings, all excluded PS 2 patients.32-34 The Canadian phase II/III trial (BR24), which randomized patients to carboplatin-paclitaxel with or without cediranib, initially included PS 2 patients.35 However, excessive toxicities were noted and, in addition to a dose adjustment, PS 2 patients were subsequently excluded from enrollment. Final data are pending at this time. In summary, at this time, there are no data to guide the use of multitargeted TKIs in patients with advanced NSCLC and a PS of 2.

Conclusion The treatment of PS 2 patients with advanced NSCLC remains challenging. Although there is a growing realization that these patients benefit from systemic chemotherapy, the optimal strategy has not yet been defined. Recent data indicate a consistent improvement in response rate and PFS for combination chemotherapy compared to single-agent therapy, without a detriment in quality of life, but a survival advantage has not been demonstrated. Recent advances in first-line therapy of advanced NSCLC, particularly with the addition of bevacizumab, have not translated into the PS 2 population. Likewise, data from trials using oral multitargeted TKIs cannot be extrapolated to PS 2 patients. With respect to EGFR inhibitors, PS 2 patients seem to benefit from salvage erlotinib, but

are best treated with chemotherapy rather than erlotinib or gefinitib in the first-line setting. Finally, although it is reassuring that PS 2 patients in the FLEX trial seem to derive a similar benefit to PS 0-1 patients, other cetuximab trials have yielded disappointing results in the PS 2 subset. Defining which therapies are best suited for PS 2 patients will require a greater investment into clinical trials specific for this patient population and the use of better clinical and predictive markers of response.36-39 A deeper understanding of the factors leading to a poor PS, such as the relationship between rapidly progressive cancer symptoms and comorbid conditions, will also guide the optimal treatment for these patients. Future areas of research include the development of better predictive biomarkers and improvements in supportive measures to enhance the therapeutic index of these agents.

Disclosures Rogerio Lilenbaum, MD, consultant or advisory role, Genentech, Inc., AstraZeneca; Estelamari Rodriguez, no disclosures.

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